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These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we showed that hypoxia-inducing anti-VEGF therapy upregulated programmed cell death ligand 1 (PD-L1), yet failed to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggered epithelial osteopontin (SPP1) production, which recruited monocytes and skewed macrophages toward M2 states, suppressing T cell cytotoxicity. Pharmacological SPP1 depletion impeded the development of hypoxia, reduced M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenics and anti\u2013PD-L1. Genetic dissection \u2014 tumor-epithelial\n                    <jats:italic>Spp1<\/jats:italic>\n                    -KO grafts and bone marrow chimeras generated by lethal irradiation and reconstitution with\n                    <jats:italic>Spp1<\/jats:italic>\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    or WT hematopoietic donors \u2014 showed that myeloid SPP1 contributed only marginally compared with epithelial SPP1. These findings identified SPP1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contributed to a comprehensive model of antiangiogenic resistance, and supported SPP1-targeted strategies to personalize immunotherapy and antiangiogenic therapy according to tumor hypoxia.\n                  <\/jats:p>","DOI":"10.1172\/jci174092","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:01:13Z","timestamp":1784052073000},"source":"Crossref","is-referenced-by-count":2,"title":["Osteopontin mediates acquired resistance to hypoxia-inducing antiangiogenics and promotes anti\u2013PD-L1 refractoriness in breast cancer models"],"prefix":"10.1172","volume":"136","author":[{"given":"Jose Luis","family":"Ruiz-Sepulveda","sequence":"first","affiliation":[{"name":"Breast Cancer Clinical Research Unit and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria 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